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1.
The increased expression of SIRT1 has recently been identified in numerous human tumors and a possible correlation with c-Myc oncogene has been proposed. However, it remains unclear whether SIRT1 functions as an oncogene or tumor suppressor. We sought to elucidate the role of SIRT1 in liver cancer under the influence of c-Myc and to determine the prognostic significance of SIRT1 and c-Myc expression in human hepatocellular carcinoma. The effect of either over-expression or knock down of SIRT1 on cell proliferation and survival was evaluated in both mouse and human liver cancer cells. Nicotinamide, an inhibitor of SIRT1, was also evaluated for its effects on liver tumorigenesis. The prognostic significance of the immunohistochemical detection of SIRT1 and c-Myc was evaluated in 154 hepatocellular carcinoma patients. SIRT1 and c-Myc regulate each other via a positive feedback loop and act synergistically to promote hepatocellular proliferation in both mice and human liver tumor cells. Tumor growth was significantly inhibited by nicotinamide in vivo and in vitro. In human hepatocellular carcinoma, SIRT1 expression positively correlated with c-Myc, Ki67 and p53 expression, as well as high á-fetoprotein level. Moreover, the expression of SIRT1, c-Myc and p53 were independent prognostic indicators of hepatocellular carcinoma. In conclusion, this study demonstrates that SIRT1 expression supports liver tumorigenesis and is closely correlated with oncogenic c-MYC expression. In addition, both SIRT1 and c-Myc may be useful prognostic indicators of hepatocellular carcinoma and SIRT1 targeted therapy may be beneficial in the treatment of hepatocellular carcinoma.  相似文献   

2.
TH Wang  KF Ng  TS Yeh  YL Wang  KH Liang  CT Yeh  TC Chen 《PloS one》2012,7(7):e41749

Background

EphrinA5, a member of Eph/Ephrin family, possesses two alternative isoforms, large ephrinA5 isoform (ephrinA5L) and small ephrinA5 isoform (ephrinA5S). EphrinA5L is a putative tumor suppressor in several types of human cancers. However, the role of ephrinA5S in hepato-carcinogenesis remains unclear. In this study, we evaluate the role of ephrinA5 isoforms in human hepatocellular carcinomas (HCC).

Methodology/Principal Findings

A total of 142 paired HCCs and peritumoral liver tissue was examined for relative expression of ephrinA5L and ephrinA5S by using quantitative real-time polymerase chain reaction. We analyzed their expression in relation to clinical parameters, disease-free survival and overall survival. Functional assays were performed to dissect the possible underlying mechanisms. Both ephrinA5L and ephrinA5S were significantly downregulated in HCCs, as compared to those in peritumoral tissue (p = 0.013 and 0.001). Univariate analysis demonstrated that ephrinA5S was positively correlated with old age and histological grade. In multivariate analysis, high ephrinA5S expression in peritumoral tissue had better disease-free survival (p = 0.002) and overall survival (p = 0.045) in patients with HCC after surgical resection. Functional analysis in HCC cell lines revealed that ephrinA5S had a more potent suppressive effect than ephrinA5L on cell proliferation (p<0.05) and migration (p<0.01). Furthermore, forced expression of both ephrinA5 isoforms in HCC cell lines significantly down-regulated epidermal growth factor receptor (EGFR) expression by promoting c-Cbl-mediated EGFR degradation.

Conclusions/Significance

EphrinA5S might be a useful prognostic biomarker for HCCs after surgical resection. EphrinA5, especially ephrinA5S, acts as a tumor suppressor in hepatocarcinogenesis. Peritumoral small ephrinA5 isoform level could determine the postoperative survival in hepatocellular carcinoma.  相似文献   

3.

Background

Gene silencing due to aberrant DNA methylation is a frequent event in hepatocellular carcinoma (HCC) and also in hepatocellular adenoma (HCA). However, very little is known about epigenetic defects in fibrolamellar carcinoma (FLC), a rare variant of hepatocellular carcinoma that displays distinct clinical and morphological features.

Methodology/Principal Findings

We analyzed the methylation status of the APC, CDH1, cyclinD2, GSTπ1, hsa-mir-9-1, hsa-mir-9-2, and RASSF1A gene in a series of 15 FLC and paired normal liver tissue specimens by quantitative high-resolution pyrosequencing. Results were compared with common HCC arising in non-cirrhotic liver (n = 10). Frequent aberrant hypermethylation was found for the cyclinD2 (19%) and the RASSF1A (38%) gene as well as for the microRNA genes mir-9-1 (13%) and mir-9-2 (33%). In contrast to common HCC the APC and CDH1 (E-cadherin) genes were found devoid of any DNA methylation in FLC, whereas the GSTπ1 gene showed comparable DNA methylation in tumor and surrounding tissue at a moderate level. Changes in global DNA methylation level were measured by analyzing methylation status of the highly repetitive LINE-1 sequences. No evidence of global hypomethylation could be found in FLCs, whereas HCCs without cirrhosis showed a significant reduction in global methylation level as described previously.

Conclusions

FLCs display frequent and distinct gene-specific hypermethylation in the absence of significant global hypomethylation indicating that these two epigenetic aberrations are induced by different pathways and that full-blown malignancy can develop in the absence of global loss of DNA methylation. Only quantitative DNA methylation detection methodology was able to identify these differences.  相似文献   

4.
5.
目的:探讨长链非编码RNA PVT1 (lncRNA-PVT1)在肝癌组织中的表达以及在肝癌诊治中的临床意义。方法:采用qRT-PCR法检测肝癌组织和癌旁肝组织中lncRNA-PVT1的表达情况,通过x2检验分析lncRNA-PVT1的表达水平与肝癌患者临床病理指标之间的相关性,采用Kaplan-Meier法绘制患者术后生存曲线,Log-rank检验比较生存率的差异,单因素和多因素分析评估影响肝癌患者预后的独立危险因素。结果:肝癌组织中lncRNA-PVT1的表达水平显著高于癌旁肝组织(P0.05)。肝癌组织lncRNA-PVT1的表达水平与其Edmondson分级、TNM分期、分化程度和是否发生血管转移具有显著相关性(P0.05),而与患者的年龄、性别、血AFP水平、肿瘤直径、肿瘤数目以及是否有肝炎病史无关(P0.05)。lncRNA-PVT1高表达组患者的术后生存率明显低于lncRNA-PVT1低表达组患者,高表达水平的lncRNA-PVT1、Edmondson分级、TNM分期、分化程度和是否发生血管转移均是影响肝癌患者预后的独立危险因素。结论:lncRNA-PVT1在肝癌组织中呈高表达,高表达水平的lncRNA-PVT1与肝癌患者的临床预后不良密切相关,有望成为今后肝癌治疗的新靶点。  相似文献   

6.
目的探讨谷氨酰胺合成酶(glutamine synthetaseGS)、E-钙粘蛋白(E—cadherin)和β-连环蛋白(β-catenin)在肝细胞癌中的表达及其与临床病理特征和预后的关系。方法采用免疫组织化学Envision法检测182例肝细胞癌和92例癌旁肝组织中GS、E-cadherin和β-catenin的表达情况,并分析其与临床病理特征和预后的关系。结果GS在肝细胞癌阳性表达率为77.5%,明显高于癌旁肝组织(4.3%),差异显著(P〈0.05);肝细胞癌E—cadherin和β-catenin异常表达率分别为59.3%和58.8%,亦高于癌旁肝组织(30.4%和26.1%),差异显著(P〈0.05)。肝细胞癌中GS的表达与TNM分期、转移和术后复发显著相关(P〈0.05);E—cadherin和β-catenin异常表达与脉管内瘤栓、TNM分期、转移和术后复发显著相关(P〈0.05)。肝细胞癌中GS表达与E-cadherin、β-catenin异常表达正相关。结论肝细胞癌中GS的高表达,与E-cadherin和β-catenin表达的下调,可能是肝细胞癌侵袭和转移的重要机制之一,联合检测GS、E-cadherin和β-catenin可能有助于判断肝细胞癌的恶性程度、转移潜能及预后分析。  相似文献   

7.
摘要 目的:探讨有机阴离子转运多肽1B3(OATP1B3)在肝细胞癌(肝癌)组织中的表达及作用。方法:通过免疫组化实验和免疫印迹试验(Western blot)检测肝癌组织及其癌旁组织中OATP1B3情况,并分析其与患者临床病理特征的相关性。采用实时荧光定量聚合酶链反应(qRT-PCR)检测OATP1B3在多株肝癌细胞中的表达情况,选择表达量相对较低的人肝癌细胞(HepG2和Huh7)细胞进行过表达实验,细胞毒实验(MTT)和流式细胞术分别检测OATP1B3对细胞增殖及凋亡的影响。结果:肝癌组织中OATP1B3表达水平明显低于癌旁组织(P<0.05),且与患者恶性肿瘤国际临床病期分类(TNM分期)、肿瘤分化程度、有无肿瘤复发显著相关(P<0.05)。过表达OATP1B3可抑制HepG2和Huh7细胞增殖,促进细胞凋亡。结论:OATP1B3在肝癌组织中低表达,上调其表达可抑制肝癌细胞增殖和促进细胞凋亡。OATP1B3可能是肝癌的抑癌基因,对肝癌的发生、发展具有重要作用。  相似文献   

8.
Adamant progression of chronic cholangiopathies towards cirrhosis and limited therapeutic options leave a liver transplantation the only effective treatment. Insulin-like growth factor 1 (IGF1) effectively blocks fibrosis in acute models of liver damage in mice, and a phase I clinical trial suggested an improved liver function. IGF1 targets the biliary epithelium, but its potential benefit in chronic cholangiopathies has not been studied. To investigate the possible therapeutic effect of increased IGF1 expression, we crossed Abcb4?/? mice (a model for chronic cholangiopathy), with transgenic animals that overexpress IGF1. The effect on disease progression was studied in the resulting IGF1-overexpressing Abcb4?/? mice, and compared to that of Abcb4?/? littermates. The specificity of this effect was further studied in an acute model of fibrosis. The overexpression of IGF1 in transgenic Abcb4?/? mice resulted in stimulation of fibrogenic processes — as shown by increased expression of Tgfß, and collagens 1, 3 and 4, and confirmed by Sirius red staining and hydroxyproline measurements. Excessive extracellular matrix deposition was favored by raise in Timp1 and Timp2, while a reduction of tPA expression indicated lower tissue remodeling. These effects were accompanied by an increase in expression of inflammation markers like Tnfα, and higher presence of infiltrating macrophages. Finally, increased number of Ck19-expressing cells indicated proliferation of biliary epithelium. In contrast to liver fibrosis associated with hepatocellular damage, IGF1 overexpression does not inhibit liver fibrogenesis in chronic cholangiopathy.  相似文献   

9.
The incidence of hepatocellular carcinoma (HCC) is closely correlated with hepatitis B virus (HBV)-induced liver cirrhosis. Structural changes in the glycans of serum and tissue proteins are reliable indicators of liver damage. However, little is known about the alteration of liver glycopatterns during cirrhosis and tumor progression induced by HBV infection. This study compared the differential expression of liver glycopatterns in 7 sets of normal pericarcinomatous tissues (PCTs), cirrhotic, and tumor tissues from patients with liver cirrhosis and HCC induced by HBV using lectin microarrays. Fluorescence-based lectin histochemistry and lectin blotting were further utilized to validate and assess the expression and distribution of certain glycans in 9 sets of corresponding liver tissue sections. Eight lectins (e.g., Jacalin and AAL) revealed significant difference in cirrhotic tissues versus PCTs. Eleven lectins (e.g., EEL and SJA) showed significant alteration during cirrhotic and tumor progression. The expression of Galα1-3(Fucα1-2)Gal (EEL) and fucosyltransferase 1 was mainly increasing in the cytoplasm of hepatocytes during PCTs-cirrhotic-tumor tissues progression, while the expression of T antigen (ACA and PNA) was decreased sharply in cytoplasm of tumor hepatocytes. Understanding the precision alteration of liver glycopatterns related to the development of hepatitis, cirrhosis, and tumor induced by HBV infection may help elucidate the molecular mechanisms underlying the progression of chronic liver diseases and develop new antineoplastic therapeutic strategies.  相似文献   

10.
目的:探讨抑癌基因p53在肝癌组织中表达及临床意义,为肝癌的治疗提供新的思路。方法:回顾性分析了2006年1月~2009年8月收治的40例肝癌患者的临床资料,采用免疫组织化学法测定肝癌组织、癌旁组织和正常组织中抑癌基因p53的表达,并分析不同肿瘤分化程度患者p53的表达。结果:p53阳性表达率在在肝癌组、癌旁组分别为47.5%和2.5%,在正常组未检测到p53阳性表达,三组之间比较有显著性差异(x2=6.515,P=0.024);高分化癌P53蛋白阳性表达率低,中低分化癌P53蛋白阳性表达率高,组比较均有显著性差异(P<0.05),中、低分化组之间比较差异无统计学意义(P>0.05)。结论:在肝癌组织中存在p53基因的高表达,其阳性表达与肿瘤分化程度有关。  相似文献   

11.
目的:研究Smoothened(SMO)在肝癌和肝硬化中的表达及临床意义。方法:选取组织标本后,运用石蜡包埋,切片后,HE染色,构建组织芯片,免疫组织化学和原位杂交方法检测Smo蛋白在肝癌和肝硬化中的表达。结果:Smo蛋白在肝癌细胞浆、良性肝肿瘤组织细胞浆、肝硬化组织中强染色,在正常组织中无染色。并且在典型肝硬化中强染色,在中度肝硬化中弱阳性。结论:Smo蛋白表达与肝癌的发生有关,Smo基因的高表达可能激活某种机制而参与诱导肝癌的发生。可能是通过异常激活Sonic hedgchog信号通路,从而诱导肝癌的发生与发展。  相似文献   

12.
Although the CD90 (Thy-1) was proposed as biomarker of several tumors and cancer stem cells, the involvement of this molecule in the progression of hepatocellular carcinoma (HCC) and other less frequent hepatic neoplasms is still undefined. The distribution of CD90 was investigated both in in vivo (human tissues samples) and in vitro (human HCC cell line JHH-6). A total of 67 liver tumors were analyzed: 51 HCC, 6 cholangiocarcinoma and 10 hepatoblastoma. In all cases, paired tissue sample of both the tumor and cirrhotic liver was available. Hepatic tissue obtained in 12 healthy livers was used as control. CD90 gene expression was studied by RT-qPCR, protein expression was assessed by quantitative Western Blot, immunofluorescence and flow cytometry. The CD90 expression analysis showed a significant increment in tumor compared to both its paired cirrhotic tissue and normal liver (p<0.05 and p<0.001, respectively). This increase was accompanied by the up-regulation of stromal component in the cancer, as demonstrated by alpha smooth muscle actin staining. In vitro analysis of JHH-6 cell line showed a higher proliferation capacity of CD90+ compared to CD90- cells (p<0.001), also noticed in 3D clonogenic assay (p<0.05), associated by a significant higher expression of the promoting factors (hepatocyte growth factor, fibroblast associated protein and alpha smooth muscle actin 2). A higher expression of the breast cancer resistance protein was found in CD90+ subpopulation while the multidrug resistance protein 1 showed an opposite behavior. Collectively, these results point to the importance of CD90 in the HCC.  相似文献   

13.
目的:探讨肝癌组织中微小RNA-338-3p(miR-338-3p)的表达及与临床病理参数的关系。方法:选取2015年1月至2016年6月我院手术获得的67例肝癌组织标本,同时每例标本均取癌旁正常组织标本作为配对对照,采用实时定量逆转录聚合酶链反应(RT-qPCR)对两组组织标本中的miR-338-3p进行检测,并分析其与肝癌临床病理特征的关系。结果:45例(67.16%)miR-338-3p表达下调,22例(32.85%)表达上调;RT-qPCR结果显示,肝癌组织中miR-338-3p的相对含量为(0.76±0.38),低于癌旁正常组织中的(1.23±0.45),差异有统计学意义(t=-6.259,P=0.000)。miR-338-3p在低分化、TNM分期Ⅲ+Ⅳ期、肿瘤浸润深度T3+T4期、有淋巴结转移肝癌患者肝癌组织中的表达下调率高于中高分化、Ⅰ+Ⅱ期、T1+T2期、无淋巴结转移肝癌患者,差异有统计学意义(P0.05)。不同性别、年龄、病理类型、肿瘤大小肝癌患者肝癌组织中miR-338-3p表达下调率差异无统计学意义(P0.05)。结论:miR-338-3P在肝癌组织中呈低表达水平,与分化程度、TNM分期、肿瘤浸润深度、淋巴结转移有关,可能参与了肝癌的发生发展过程,早期检测可作为评估肝癌病情的指标。  相似文献   

14.
Expression of MACC1 (metastasis-associated in colon cancer-1) protein is associated with metastasis of various human cancers. This study analyzed MACC1 protein expression in hepatocellular carcinoma (HCC) tissue specimens and then investigated the effects of MACC1 knockdown on HCC cell migration and invasion, and gene expression levels. Sixty pairs of HCC and adjacent normal liver tissues from HCC patients were analyzed for MACC1 expression immunohistochemically. The HCC cell lines Hep3B, Huh7, MHCC97H, SMMC-7721, Bel-7402, and HepG2 and the normal liver cell line LO2 were used to assess expressions of MACC1 mRNA and MACC1 protein using qRT-PCR and western blot, respectively. MACC1 short hairpin RNA (shRNA) was used to knockdown MACC1 protein expression in Huh7 cells. Changes in the tumor phenotype of these cells were analyzed with wound healing assay and invasion assays, and differences in gene expression were evaluated via western blot. Immunofluorescence was used to locate MACC1 protein in the above cell lines. MACC1 was highly expressed in HCC tissues and the nuclear expression of MACC1 protein was associated with poor tumor differentiation and intrahepatic metastasis or portal invasion. Moreover, MACC1 mRNA and MACC1 protein was also expressed in HCC cell lines. Immunostaining showed that MACC1 protein was localized in both nuclei and cytoplasm of HCC cell lines and the nuclear localization of MACC1 protein was associated with increased aggressiveness of HCC in cell lines. Knockdown of MACC1 expression using MACC1-shRNA reduced Huh7 cell migration and invasion abilities, which was associated with downregulation of MMP2, MMP9, and c-Met proteins in Huh7 cells. Localization of MACC1 protein to the nucleus may predict HCC progression. Knockdown of MACC1 expression using MACC1 shRNA warrants further evaluation as a novel therapeutic strategy for control of HCC.  相似文献   

15.
Bisphenol A (BPA) is an endocrine disrupting chemical (EDC) that has been implicated as a potential carcinogen and epigenotoxicant. We have previously reported dose-dependent incidence of hepatic tumors in 10-month-old isogenic mice perinatally exposed to BPA. Here, we evaluated DNA methylation at 3 candidate genes (Esr1, Il-6st, and Stat3) in liver tissue of BPA-exposed mice euthanized at 2 time points: post-natal day 22 (PND22; n = 147) or 10-months of age (n = 78, including n = 18 with hepatic tumors). Additionally, DNA methylation profiles were analyzed at human homologs of murine candidate genes in human fetal liver samples (n = 50) with known liver tissue BPA levels. Candidate genes were chosen based on reported expression changes in both rodent and human hepatocellular carcinoma (HCC). Regions for bisulfite sequencing were chosen by mining whole genome next generation sequencing methylation datasets of both mice and human liver samples with known perinatal BPA exposures. One of 3 candidate genes, Stat3, displayed dose-dependent DNA methylation changes in both 10-month mice with liver tumors as compared to those without liver tumors and 3-week sibling mice from the same exposure study, implicating Stat3 as a potential epigenetic biomarker of both early life BPA exposure and adult disease in mice. DNA methylation profiles within STAT3 varied with liver tissue BPA level in human fetal liver samples as well, suggesting STAT3 may be a translationally relevant candidate biomarker. These data implicate Stat3 as a potential early life biomarker of adult murine liver tumor risk following early BPA exposure with early evidence of relevance to human health.  相似文献   

16.
17.
To investigate the clinical significance of 128 slice whole liver four dimensional computed tomography (4D CT) in diagnosis and differential diagnosis of hepatic disease, by characterizing and comparing perfusion maps in two common hepatic tumors: hepatocellular carcinoma (HCC) and liver hemangioma. 45 patients with HCC and 40 patients with liver hemangioma were subjected to 128 slice 4D CT of the whole liver perfusion scan, perfusion images were obtained, and data were processed by the perfusion software. Four perfusion parameters generated automatically were used to characterize and compare the perfusion of tumor tissue and surrounding hepatic parenchyma: blood flow perfusion (BF), arterial liver perfusion (ALP), portal venous perfusion (PVP), and hepatic perfusion index (HPI). Volumetric CT perfusion data then reconstructed to yield 4D CT angiography. Morphological observation was made regarding to the blood supply of tumor, intrahepatic vasculature. (1) In both HCC and hepatic hemangioma, BF, ALP, HPI were higher (P < 0.01), whereas PVP were lower (P < 0.01) in tumor tissue than the surrounding hepatic parenchyma (within 1 cm of lesion). Compared with liver hemangioma tumor tissue, BF, ALP, PVP were lower in HCC tumor tissue (P < 0.05; 0.01; 0.01), but HPI is higher (P < 0.05). For the perfusion of the surrounding parenchyma, BF and ALP were higher (P < 0.001), PVP was lower (P < 0.001) in HCC, while HPI was unchanged. (2) Among 45 cases with HCC, cancer feeding artery was found in 28 cases. In 20 cases feeding artery was shown as thickening, rigid, or distorted. Tumor thrombus in portal vein was found in 14 cases. For total of 40 cases with liver hemangioma, in 23 cases blood vessels are shifted due to compression from tumor mass, the rest 17 cases show normal vasculature. With application of 128 slice 4D CT, whole liver perfusion scan can reliably reflect the hemodynamic characteristics of HCC and hepatic hemangioma, proving to be a valuable adjunct to conventional imaging techniques of liver for early detection, differential diagnosis, and determining surgical resection range as well as estimating prognosis for hepatic tumors.  相似文献   

18.
Background AMP-deaminase (EC 3.5.4.6) is an enzyme of nucleotide breakdown involved in regulation of energetic metabolism in mammalian cells. The enzyme is coded by a family of three independent genes (AMPD1, AMPD2 and AMPD3), synthesizing three different isozymes. In mammalian liver, the reaction catalyzed by AMP-deaminase constitutes a rate-limiting step in adenine nucleotide catabolism. In neoplastic liver, adenine nucleotide catabolism is a subject of many modifications, which influence the expression of genes synthesizing enzymes regulating this pathway. Aims The experimental studies presented here illustrate the expression of AMPD genes in human liver neoplasm tumor (HCC, hepatocellular carcinoma). Methods RT-PCR and Western blotting methods were used for determining of the goal mentioned above. Results and conclusion Expression level of AMPD gene family in the tumorous fragment (HCC tumor) of neoplastic liver did not differ substantially from that found in the nontumorous (cirrhotic) fragment of the organ. In this case the expression of AMPD2 gene was prevailing. AMPD2 was the main isoform of AMP-deaminase identified in two liver fragments compared. This is a first report evidencing the pattern of AMPD genes expression in neoplastic human liver.  相似文献   

19.
Wu LM  Yang Z  Zhou L  Zhang F  Xie HY  Feng XW  Wu J  Zheng SS 《PloS one》2010,5(12):e14460

Background

Recent studies have shown that high expression levels of class I histone deacetylases (HDACs) correlate with malignant phenotype and poor prognosis in some human tumors. However, the expression patterns and prognostic role of class I HDAC isoforms in hepatocellular carcinoma (HCC) remain unclear.

Methodology/Principal Findings

The expression patterns and clinical significance of class I HDAC isoforms were assessed by immunohistochemistry in a cohort of 43 hepatitis B virus-associated HCC patients treated with liver transplantation. In addition, the effects of HDAC inhibition on HCC cell behavior were investigated by knockdown of the HDAC isoform with short interfering RNA. Class I HDACs were highly expressed in a subset of HCCs with positivity for HDAC1 in 51.2%, HDAC2 in 48.8%, and HDAC3 in 32.6% of cases. The expression levels of HDAC isoforms were significantly associated with the proliferation index of HCC. Kaplan-Meier curves showed that a high expression level of HDAC2 or HDAC3 implicated significantly reduced recurrence-free survival. Cox proportional hazards model analysis revealed HDAC3 overexpression was an unfavorable independent prognostic factor (P = 0.002; HR 3.907). In vitro, inhibition of HDAC2 and HDAC3, but not HDAC1, suppressed proliferation and the invasiveness of liver cancer cells.

Conclusions/Significance

Our findings demonstrate that HDAC3 plays a significant role in regulating tumor cell proliferation and invasion, and it could be served as a candidate biomarker for predicting the recurrence of hepatitis B virus-associated HCC following liver transplantation and a potential therapeutic target.  相似文献   

20.
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